The ability to identify different chemicals is a ubiquitous feature of most animals, from primitive roundworms to mammals. The most important feeding decisions animals have to make is to discriminate between palatable tasty food chemicals, such as sugars, and aversive, bitter tasting and possibly toxic chemicals. A second more elaborate process is the identification of food best suited for a specific condition, such as overall nutrition status (hunger vs. satiation), anticipated need for major energy expenditure (locomotion), a developmental stage or reproductive phase. To accommodate these needs, gustatory systems have evolved sensors for the identification of different types of nutrients. In this application, we will investigate the functions of a highly conserved Drosophila Gustatory receptor (Gr) gene subfamily in sensing biomolecules. Specifically, we present strong evidence that implicates the Gr28 gene family (Gr28a, Gr28b.a-b.e) in the perception of RNA through its ribose moiety. We show that Drosophila larvae are highly attracted to RNA/ribose, a preference entirely dependent on the presence of the Gr28 genes. Using a novel Ca2+ indicator (CaMPARI), we establish that RNA, ribose and uridine activate taste neurons expressing Gr28a. We also show that RNA, but not DNA is necessary for normal growth and survival during larval development. This is the first association of Gr genes with a direct chemosensory function in the detection of large biomolecules. We hypothesize that the Gr28 proteins recognize RNA precursor and other ribose containing compounds both externally and internally. Thus, this proposal will likely establish a molecular mechanism not only for the detection of exogenous RNA related nutrients, but also for the previously reported roles for these receptors in light and temperature sensing. Drosophila has been the major non-vertebrate model system in the study of taste sensory perception, as it provides a range of molecular genetic tools that can be employed in both cellular and whole animal assays, such as electrophysiological recordings and Ca2+ imaging on taste neurons and behavioral analyses. While the receptors (at least for sugar and bitter compounds) are evolutionarily not conserved between mammals and insects, the organization of the gustatory systems and the logic of taste coding in these diverse animal phyla are remarkably similar. Moreover, the use of taste receptors in postprandial nutrient sensing (either in the gut or the brain) has been reported in both systems, and likely plays important roles in feeding regulation. Thus, this work will have a significant impact on fundamental principles of conserved chemosensory processes.